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>OLYVINYL CHLORIDE ehP .ENVIRONMENTAL HEALTH PERSPECTIVES U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service-National Institutes of Health National Institute of Environmental Health Sciences * VOLUME 41, OCTOBER 1981 RNW20187 SUBSCRIPTION INFORMATION Subscription rates are as follows: Single copies $7.00, foreign $8.75, domestic $41.00 per year, foreign $51.25 per year. The yearly subscription is for 6 regular issues. Please send check or money order, in advance to the Superintendent of Docu ments, U.S. Government Printing Office, Washing ton, D.C. 20402. The Secretary of Health and Human Services has determined that the publication of this periodical is necessary in the transaction of the public business required by law of this Department. Use of funds for printing this periodical has been approved by the Director of the Office of Management and Budget through January 31, 1983. ENVIRONMENTAL HEALTH PERSPECTIVES is a publication of the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services. Opinions expressed herein, however, are not necessarily endorsed nor shared by any of the above agencies. 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Dockery, Assistant Managing Editor Ruth Krigman, Copy Editor Sharon Barber ENVIRONMENTAL HEALTH PERSPECTIVES Volume 41, October 1981 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health RNW20189 CONTENTS Conference to Reevaluate the Toxicity of Vinyl Chloride, Poly(vinyl Chloride) and Structural Analogs R. J. Waxweiler, P. J. Landrigan, P. Infante and R. Shapiro. Introduction ......... C. Maltoni, G. Lefemine, A. Ciliberti, G. Cotti and D. Carretti. Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis ............................................................................................................................... Y. Suzuki. Neoplastic and nonneoplastic effects of vinyl chloride in mouse lung ..... D. H. Groth, W. B. Coate, B. M. Ulland and R. W. Hornung. Effects of aging on the induction of angiosarcoma ............................................................................................ M. J. Radike, K. L. Stemmer and E. Bingham. Effect of ethanol on vinyl chloride carcinogenesis ................................................................................................................ R. M. Hehir, B. P. McNamara, J. McLaughlin, Jr., D. A. Willigan, G. Bierbower and J. F. Hardisty. Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer .............................................................. D. H. Groth, D. W. Lynch, W. J. Moorman, L. E. Stettler, T. R. Lewis, W. D. Wagner and C. Kommineni. Pneumoconiosis in animals exposed to polyfvinyl chloride) dust.................................................................................................................. J. C. Wagner and N. F. Johnson. Preliminary observations of the effect of inhalation of PVC in man and experimental animals .................................................................. C. Maltoni and P. Lodi. Results of sputum cytology7 among workers exposed to vinyl chloride monomer and to poly(vinyl chloride) ............................................................ P. F. Infante. Observations of the site-specific carcinogenicity of vinyl chloride to humans ............................................................................................................................ H. Weber, W. Reinl and E. Greiser. German investigations on morbidity and mortality of workers exposed to vinyl chloride ......................................................... W. C. Cooper. Epidemiologic study of vinyl chloride workers: mortality through December 31, 1972 ........................................................................................................ H. Falk, J. Herbert, S. Crowley, K. G. Ishak, L. B. Thomas, H. Popper and G. G. Caldwell. Epidemiology of hepatic angiosarcoma in the United States: 1964-1974 .... P. J. Baxter. The British Hepatic Angiosarcoma Register ......................................... C. H. Tamburro and R. Greenberg. Effectiveness of federally required medical laboratory screening in the detection of chemical liver injury .................................. R. N. Wheeler, Jr. Poly(vinyl chloride) processes and products ................................. J. H. Jones. Worker exposure to vinyl chloride and poly(vinyl chloride) ................... L. Chiazze, Jr., and L. D. Ference. Mortality among PVC-fabricating employees .... G. Molina, B. Holmberg, S. Elofsson, L. Holmlund, R. Moosing and P. Westerholm. Mortality and cancer rates among workers in the Swedish PVC processing industry........................................................................................................ G. Mastrangelo, B. Saia, G. Marcer and G. Piazza. Epidemiological study of pneumoconiosis in the Italian poly(vinyl chloride) industry ...................................... R. J. Waxweiler, A. H. Smith, H. Falk and H. A. Tyroler. Excess lung cancer risk in a synthetic chemicals plant........................................................................................... R. Lilis. Review of pulmonary effects of poly(vinvl chloride) and vinyl chloride exposure ......................................................................................................................... 1 3 31 53 59 63 73 83 85 89 95 101 107 115 117 123 129 137 145 153 159 167 RNW20190 J. A. John, F. A. Smith and B. A. Schwetz. Vinyl chloride: inhalation teratology study in mice, rats and rabbits .................................................................................... J. M. Rice. Prenatal susceptibility to carcinogenesis by xenobiotic substances including vinyl chloride.................................................................................................. J. D. Fabricant and M. S. Legator. Mutagenicity studies of vinyl chloride ............. M. Hatch, J. Kline and Z. Stein. Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs ................................................ W. F. Dimmick. EPA programs of vinyl chloride monitoring in ambient air ........... N. J. Vianna, J. Brady and P. Harper. Angiosarcoma of the liver: a signal lesion of vinyl chloride exposure.................................................................................................. K. C. Chu and H. A. Milman. Review of experimental carcinogenesis by compounds related to vinyl chloride................................................................................................ R. Apfeldorf and P. J. Infante. Review of epidemiologic study results of vinyl chloride-related compounds .......................................................................................... D. Hattis. Needs for public health intervention and needs for new research on vinyl halides and their polymers: a public policy perspective ............................................ 171 179 189 195 203 207 211 222 227 Contributed Articles R. M. Stern. Process-dependent risk of delayed health effects for welders .............. J. H. Ware, L. A. Thibodeau, F. E. Speizer, S. Colome and B. G. Ferris, Jr. Assessment of the health effects of atmospheric sulfur oxides and particulate matter: evidencefrom observational studies................................................................ R. Jourmard, M. Chiron, R. Vidon, M. Maurin and J.-M. Rouzioux. Mathematical models of the uptake of carbon monoxide on hemoglobin at low carbon monoxide levels ............................................................................................................................... J. C. Westman and J. R. Walters. Noise and stress: a comprehensive approach .... 235 255 277 291 Erratum ..................................................................................................................................... Previous volumes of EHP ...................................................................................................... 311 312 RNW20191 IN THE NEXT ISSUE A Symposium on Environmental Epidemiology N. A. Esmen. Limitations on dose estimation. Y. Alarie. Dose response analysis in animal studies: prediction of human responses. C. E. Land. Statistical limitations in relation to sample size. B. Altshuler. Modeling of dose-response relationships. H. E. Griffen. Discussion: Detection of health effects of exposure to low doses of agents--epidemiologic problems. M. A. Schneiderman. Extrapolation from incomplete data to total or lifetime risks at low doses. P. E. Enterline. Extrapolation from occupational studies--a substitute for environmental epidemiology. E. P. Radford. Sensitivity of health end points: effect on conclusions of studies. R. J. Waxweiler. Epidemiologic problems associated with exposure to several agents. P. E. Enterline. Discussion: Policy issues in applying epidemiologic evidence. V. R. Hunt. Epidemiological studies for regulatory agencies. M. Bundy. When are studies adequate for regulatory purposes: view of one regulated. I. H. Billick. Lead: a case study in interagency policy-making. L. H. Kuller. Who should provide research initiative and support? J. H. Turner Discussion: New approaches to detecting low-dose effects. N. L. Petrakis. Genetic-environmental interactions in relation to low dose stud ies. A possible model from breast cancer. J. C,, Christian. Use of twins to study environmental effects. M. K. Conner. Chromosomal methods in population studies. V. Hunt. Discussion: Epidemiologic investigation of special groups. E. A. Murphy. Detection of genetic effects of environmental agents. J. Kline. Epidemiologic detection of low dose effects on the developing fetus. C. K. Redmond. Sensitive population subsets in relation to effects of low doses. Contributed Articles J. I. Rader. Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats. B. E. Vaughan. Problems in evaluating radiation dose via terrestrial and aquatic pathways. F. Perera. The carcinogenicity of airborne fine particulate benzo(a)pyrene: an appraisal of the evidence and the need for control. RNW20192 J. Miller. Cadmium, lead and zinc in growing rats fed corn leaf tissue grown on soil amended with sewage sludge or heavy metal salts. S. Lan. Effect of air pollution on chronic respiratory disease in the New York City metropolitan area, 1972. RNW20193 Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer, Poly(vinyl Chloride) and Structural Analogs National Institutes of Health, Bethesda, MD March 20-21, 1980 Sponsored by National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health and Occupational Safety and Health Administration RNW20194 Environmental Health Perspective* Vol. il.p. 1. 19S1 Introduction It has been over 30 years since the first sugges tive evidence was published by Tribukh to indicate that vinyl chloride monomer (VCM) is acutely toxic in man. Chronic toxicity in animals was subse quently demonstrated by Torkelson in 1961, but it was an outbreak to VGM-induced acroosteolysis in the 1960's that focused attention for the first time on the occupational toxicity of this important indus trial chemical. The carcinogenicity of VCM was recognized in 1974 following the nearly simulta neous reports of an association between exposure to VCM and angiosarcoma of the liver (ASL) in man (reported by Creech and Johnson) and in animals (reported by Maltoni). These reports precipitated a thorough international review of the toxicity of VCM at the New York Academy of Sciences. Since then, enormous research efforts have been under taken to expand our knowledge of the toxicity of vinyl chloride. Many of the research efforts stimu lated by the events of the 1970's have now come to fruition, and are appropriately brought together in these proceedings. The proceedings begin with a presentation of the most extensive animal research on the carcinoge nicity of VCM ever published. In these data, dose-response curves can be examined by site and type of tumor, by route and schedule of exposure, and by species and strain of animal. This study and other research on the carcinogenicity of VCM reported in this volume indicate the importance of cofactors such as age at exposure and simultaneous exposure to ethyl alcohol in VCM toxicity. Evi dence that even a single exposure to VCM induces experimental neoplasia is significant from the stand point of both occupational and nonoccupational exposures. The updated epidemiologic studies presented in this volume of mortality among workers exposed to vinyl chloride reinforce the laboratory findings of multisite carcinogenicity. Data demonstrating the mutagenic and transplacental effects of VCM are also updated and summarized. The lack of predictivity of one prospective liver screening program sug gests the need for further work in identifying effective medical surveillance techniques for early recognition of liver abnormalities. While thousands of workers are exposed to VCM vapor, many more are exposed to its polymer, poly(vinyl chloride) (PVC). The carcinogenicity of PVC dust is evaluated both experimentally and epidemiologically in these proceedings. The results are not definitive. Nonmalignant respiratory sys tem effects from PVC dust are suggested by a number of papers at this conference. Finally, the extension of the findings of carcino genicity of VCM to its structural analogs, vinylidene chloride, trichloroethylene and tetrachloroethylene, and its brominated equivalent, vinyl bromide, serves as another lead in our effort to understand some fundamental concepts of chemical carcinogenesis. Richard J. Waxweiler Philip J. Landrigan Peter Infante Raymond Shapiro October 1981 RNW20195 Environmental Health Perspectives Vol. 41, pp. 3-29, 1981 Carcinogenicity Bioassays of Vinyl Chloride Monomer: A Model of Risk Assessment on an Experimental Basis by Cesare Maltoni,* Giuseppe Lefemine,* Adriano Ciliberti,* Giuliano Cotti* and Donata Carretti* Data are presented regarding the final results of the Bentivoglio (Bologna) project on long-term carcinogenicity bioassays of vinyl chloride (VC). The experimental project studied the effects of the monomer, administered by different routes, concentrations and schedules of treatment, to animals (near 7000) of different species, strains, sex and age. To our knowledge this is the largest experimental carcinogenicity study performed on a single compound by a single institution. The results indicate that VC is a multipotential carcinogen, affecting a variety of organs and tissues. In the experimental conditions studied, the neoplastic effects of the monomer were also detected at low doses. The experimental and biological factors greatly affect the neoplastic response to VC. Long-term carcinogenicity bioassays are. at present, a unique tool for the identification and quantification of environmental and occupational risks. Precise and highlystandardized experimental procedures are needed to obtain data for risk assessment. Introduction The present report deals with the presentation of the final results of our project on the long-term carcinogenicity bioassays of vinyl chloride (VC) (BT project). To our knowledge this project is the most exten sive experimental carcinogenesis study ever per formed on one industrial compound by a single institution. Planning, Materials, Methods and Performance of the Experiment Planning The experiments of the project were planned (a) to test the carcinogenicity of the compound; `Institute of Oncology and Tumor Center, Bologna, Italy. (b) to obtain information on the site and type of tumors; (c) to evaluate the possible effects of the routes of administration, with particular regard to the ones reproducing potential human exposure; (d) to assess, in quantitative terms, the level of risk. The planning of the experiments was aimed at achieving these goals. The compound was tested on animals of different species, strain, sex and age (Table 1), since it is known that these factors may modify the neoplastic response qualitatively and quantitatively. The choice of the animals was made with the intention of having an integrated system of complementary biological models which could express a range, as wide as possible, of neoplastic responses. VC was administered by different routes: intraperitoneal (IP) injection, subcutaneous (SC) injec tion, inhalation and ingestion (by stomach tube), the latter two being the major routes of potential human exposure. The monomer was administered at different concentrations: 14 by inhalation levels and 6 inges tion levels for various periods of time, by continu ous or intermittent treatment (Table 2). October 1981 3 RNW20196